LincRNA-p21 regulates neointima formation, vascular smooth muscle cell proliferation, apoptosis, and atherosclerosis by enhancing p53 activity

Gengze Wu, Jin Cai, Yu Han, Jinghai Chen, Zhan Peng Huang, Caiyu Chen, Yue Cai, Hefei Huang, Yujia Yang, Yukai Liu, Zaicheng Xu, Duofen He, Xiaoqun Zhang, Xiaoyun Hu, Luca Pinello, Dan Zhong, Fengtian He, Guo Cheng Yuan, Da Zhi Wang, Chunyu Zeng

Research output: Contribution to journalArticlepeer-review

432 Scopus citations

Abstract

Background: Long noncoding RNAs (lncRNAs) have recently been implicated in many biological processes and diseases. Atherosclerosis is a major risk factor for cardiovascular disease. However, the functional role of lncRNAs in atherosclerosis is largely unknown. Methods and Results: We identified lincRNA-p21 as a key regulator of cell proliferation and apoptosis during atherosclerosis. The expression of lincRNA-p21 was dramatically downregulated in atherosclerotic plaques of ApoE-/-mice, an animal model for atherosclerosis. Through loss- and gain-of-function approaches, we showed that lincRNA-p21 represses cell proliferation and induces apoptosis in vascular smooth muscle cells and mouse mononuclear macrophage cells in vitro. Moreover, we found that inhibition of lincRNA-p21 results in neointimal hyperplasia in vivo in a carotid artery injury model. Genome-wide analysis revealed that lincRNA-p21 inhibition dysregulated many p53 targets. Furthermore, lincRNA-p21, a transcriptional target of p53, feeds back to enhance p53 transcriptional activity, at least in part, via binding to mouse double minute 2(MDM2), an E3 ubiquitin-protein ligase. The association of lincRNA-p21 and MDM2 releases MDM2 repression of p53, enabling p53 to interact with p300 and to bind to the promoters/enhancers of its target genes. Finally, we show that lincRNA-p21 expression is decreased in patients with coronary artery disease. Conclusions: Our studies identify lincRNA-p21 as a novel regulator of cell proliferation and apoptosis and suggest that this lncRNA could serve as a therapeutic target to treat atherosclerosis and related cardiovascular disorders.

Original languageEnglish
Pages (from-to)1452-1465
Number of pages14
JournalCirculation
Volume130
Issue number17
DOIs
StatePublished - 2014
Externally publishedYes

Keywords

  • Apoptosis
  • Atherosclerosis
  • Cell proliferation
  • Long noncoding
  • MDM2 protein
  • RNA
  • Tumor suppressor protein p53

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